A role for cytomegalovirus-specific CD4 super(+) CX3CR1 super(+) T cells and cytomegalovirus-induced T-cell immunopathology in HIV-associated atherosclerosis

• Published in: AIDS (London) Vol. 26; no. 7; pp. 805 - 814
• Main Authors: Sacre, K, Hunt, P W, Hsue, P Y, Maidji, E, Martin, J N, Deeks, S G, Autran, B, McCune, J M
• Format: Journal Article
• Language: English
• Published: 01.01.2012
• Subjects: Arteriosclerosis; Carotid artery; CD4 antigen; Cell migration; Chemokine receptors; CX3CR1 protein; Cytokines; Cytomegalovirus; Endothelial cells; Feedback; Human immunodeficiency virus; Infection; Inflammation; Lymphocytes T; Myocardial infarction; Peripheral blood mononuclear cells
• ISSN: 0269-9370
• DOI: 10.1097/QAD.0b013e328351f780

Objective: HIV-infected individuals are at increased risk for myocardial infarction. Given observations that cytomegalovirus (CMV) infection, CMV-specific T cells, and CX3CR1 have each been associated with atherosclerosis, we hypothesized that CMV-induced T-cell immunopathology could contribute to HIV-associated atherosclerosis. Methods: We measured the expression of CX3CR1 on peripheral blood mononuclear cells and its association with carotid artery intima-media thickness (IMT) in 29 HIV-infected individuals and 48 uninfected controls. We analyzed the phenotype and specificity of CX3CR1 super(+)CD4 super(+) T cells, the production of CX3CL1 (the ligand of CX3CR1) by CMV-infected endothelial cells in vitro, and the migration of CD4 super(+) T cells induced by CX3CL1. Results: The progression of atherosclerosis in HIV-infected individuals, as assessed by longitudinal measurements of carotid IMT, was associated with a high frequency of CD4 super(+) T cells that express the chemokine receptor CX3CR1. Such CD4 super(+)CX3CR1 super(+) T cells were antigen-primed, produced high levels of pro-inflammatory cytokines, and composed the majority of the CMV-specific CD4 super(+) T cells. CMV-stimulated CD4 super(+) T cells were also found to induce the production of CX3CL1 (the ligand for CX3CR1) by human arterial endothelial cells, driving the transendothelial migration of pro-inflammatory CD4 super(+) T cells. Finally, we observed that CD4 super(+)CX3CR1 super(+) T cells could be localized to the coronary arterial wall in HIV disease. Conclusion: HIV-associated atherosclerosis may be driven by a positive feedback pathway in which a high frequency of antigen-stimulated, CMV-specific CD4 super(+)CX3CR1 super(+) T cells induce endothelial cells to secrete CX3CL1, which itself drives progressive infiltration of the arterial wall by pro-inflammatory cells.